BERENICE: A Study Evaluating Pertuzumab (Perjeta) Combined With Trastuzumab (Herceptin) and Standard Anthracycline-based Chemotherapy in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Locally Advanced, Inflammatory, or Early-stage Breast Cancer

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02132949
• Collaborator: (none)
• Enrollment: 401
• Locations: 80
• Arms: 2
• Actual Duration (Months): 73.4
• Patients Per Site: 5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This multicenter, non-randomized, open-label, phase 2 study is designed to evaluate the safety and efficacy of pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and anthracycline-based chemotherapy as neoadjuvant treatment in participants with HER2-positive locally advanced, inflammatory, or early-stage breast cancer. Each investigator will choose a treatment regimen (A or B) for all of their participants to follow. Treatment regimen A (for Cohort A) will include dose-dense doxorubicin and cyclophosphamide (ddAC), followed by paclitaxel, with pertuzumab and trastuzumab given from the start of paclitaxel. Treatment regimen B (for Cohort B) will include 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), followed by docetaxel, with pertuzumab and trastuzumab given from the start of docetaxel. Participants in both cohorts will subsequently undergo surgical treatment and then resume pertuzumab and trastuzumab treatment.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: 5-Fluorouracil; Drug: Cyclophosphamide; Drug: Docetaxel; Drug: Doxorubicin; Drug: Epirubicin; Drug: Paclitaxel; Drug: Pertuzumab; Drug: Trastuzumab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 401 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Multinational, Phase II Study to Evaluate Perjeta in Combination With Herceptin and Standard Neoadjuvant Anthracycline-Based Chemotherapy in Patients With HER2-Positive, Locally Advanced, Inflammatory, or Early-Stage Breast Cancer
• Actual Study Start Date: Jul 14, 2014
• Actual Primary Completion Date: Mar 3, 2016
• Actual Study Completion Date: Aug 25, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Drug: Cyclophosphamide; Participants will receive cyclophosphamide 600 milligrams per square meter (mg/m^2) intravenous (IV) given on Day 1 of each cycle q2w.; Drug: Doxorubicin; Participants will receive doxorubicin 60 mg/m^2 IV on Day 1 of each cycle q2w.; Drug: Paclitaxel; Participants will receive paclitaxel 80 mg/m^2 IV given weekly.; Drug: Pertuzumab; Participants will receive pertuzumab at a loading dose of 840 milligrams (mg) IV loading dose, then 420 mg IV q3w.; Other Names: Perjeta ; Drug: Trastuzumab; Participants will receive trastuzumab at a loading dose of 8 milligrams per kilogram (mg/kg) IV, then 6 mg/kg IV q3w.; Other Names: Herceptin
Experimental: Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Drug: 5-Fluorouracil; Participants will receive 5-fluorouracil 500 mg/m^2 IV on Day 1 of each cycle q3w.; Drug: Cyclophosphamide; Participants will receive cyclophosphamide 600 milligrams per square meter (mg/m^2) intravenous (IV) given on Day 1 of each cycle q2w.; Drug: Docetaxel; Participants will receive docetaxel at a starting dose of 75 mg/m^2 IV for the first cycle and the dose may be escalated to 100 mg/m^2 for subsequent cycles q3w.; Drug: Epirubicin; Participants will receive epirubicin 100 mg/m^2 IV on Day 1 of each cycle q3w.; Drug: Pertuzumab; Participants will receive pertuzumab at a loading dose of 840 milligrams (mg) IV loading dose, then 420 mg IV q3w.; Other Names: Perjeta ; Drug: Trastuzumab; Participants will receive trastuzumab at a loading dose of 8 milligrams per kilogram (mg/kg) IV, then 6 mg/kg IV q3w.; Other Names: Herceptin

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Neoadjuvant Treatment Period [From day of first dose of pertuzumab or trastuzumab until the end of the neoadjuvant treatment period (as defined in the description; up to 25 weeks)]

   Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method. Results included events with onset from first dose of pertuzumab/trastuzumab prior to surgery through the day before the first dose of any study drug after surgery. If participant withdrew without entering adjuvant period, results included all events with onset from first dose of pertuzumab/trastuzumab through 42 days after last dose of any study drug or on the day of target surgery whichever was later.

2. Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Neoadjuvant Treatment Period [From day of first dose of pertuzumab or trastuzumab until the end of the neoadjuvant treatment period (as defined in the description; up to 25 weeks)]

   LVEF significant decline was defined as the decline in LVEF of >/= 10%-points from baseline to an LVEF of < 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method. Results include events with onset from the first dose of pertuzumab or trastuzumab prior to surgery through the day before the first dose of any study drug after surgery. If participant withdrew without entering adjuvant period, results included all events with onset from first dose of pertuzumab or trastuzumab through 42 days after last dose of any study drug or on the day of target surgery whichever is later.

Secondary Outcome Measures

1. Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Adjuvant Treatment Period [From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks)]

   Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method. Results included events with onset from the first dose of any study drug after surgery through 42 days after the last dose of any study drug.

2. Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Adjuvant Treatment Period [From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks)]

   LVEF significant decline was defined as the decline in LVEF of >/= 10%-points from baseline to an LVEF of < 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals were calculated using the Clopper-Pearson method. Results included events with onset from the first dose of any study drug after surgery through 42 days after the last dose of any study drug.

3. Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Treatment-Free Follow-Up Period [From 42 days after the last dose of study treatment until the end of treatment-free follow-up (up to 5 years)]

   Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method.

4. Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Treatment-Free Follow-Up Period [From 42 days after the last dose of study treatment until the end of treatment-free follow-up (up to 5 years)]

   LVEF significant decline was defined as the decline in LVEF of >/= 10%-points from baseline to an LVEF of < 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals were calculated using the Clopper-Pearson method.

5. Overview of the Number of Participants With at Least One Adverse Event During the Neoadjuvant Period [From first dose of any study drug prior to surgery through the day before the first dose of study drug after surgery (up to 25 weeks)]

   An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous with respect to an AE. Severity refers to the intensity of an AE (rated according to NCI-CTCAE v4.0 criteria or, if not listed, the following scale: Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), whereas a serious AE (SAE) is a significant medical event (per standard criteria). Severity and seriousness needed to be independently assessed for each AE that was recorded. Selected AEs for reporting included heart failure (NYHA Class II/III/IV) and asymptomatic declines in LVEF (reported as an AE with the term of ejection fraction decreased). In the results table, multiple occurrences of the same AE in one individual were counted only once. Any AE includes all serious and non-serious AEs.

6. Overview of the Number of Participants With at Least One Adverse Event During the Adjuvant Period [From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks)]

   An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous with respect to an AE. Severity refers to the intensity of an AE (rated according to NCI-CTCAE v4.0 criteria or, if not listed, the following scale: Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), whereas a serious AE (SAE) is a significant medical event (per standard criteria). Severity and seriousness needed to be independently assessed for each AE that was recorded. Selected AEs for reporting included heart failure (NYHA Class II/III/IV) and asymptomatic declines in LVEF (reported as an AE with the term of ejection fraction decreased). In the results table, multiple occurrences of the same AE in one individual were counted only once. Any AE includes all serious and non-serious AEs.

7. Overview of the Number of Participants With at Least One Adverse Event During the Treatment-Free Follow-Up Period [From 42 days after the last dose of study treatment until the end of treatment-free follow-up (TFFU; up to 5 years)]

   An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an AE (rated according to NCI-CTCAE v4.0 criteria or, if not listed, the following scale: Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), and a serious AE (SAE) is a significant medical event (per standard criteria). Severity and seriousness were independently assessed for each AE. Selected AEs for reporting included heart failure (NYHA Class II/III/IV) and asymptomatic declines in LVEF (reported as ejection fraction decreased). During TFFU, only heart failure, pregnancies, and non-breast-related second primary malignancies, irrespective of causal relationship with study treatment, and drug-related SAEs were reported. Multiple occurrences of the same AE in 1 subject were counted only once.

8. Percentage of Participants Positive for Anti-Therapeutic Antibodies (ATAs) to Pertuzumab at Baseline and Anytime Post-Baseline [Screening (baseline) then prior to pertuzumab infusion (Hour 0) in Cycles 5, 14, 18 thereafter anytime between Cycle 8 Day 21 and surgery, up to treatment completion visit (cycle length=2-3 weeks; up to approximately 1 year, 3 months)]

   ATAs to pertuzumab in serum samples were detected using a validated bridging enzyme-linked immunosorbent assay (ELISA) method. This analysis only included participants with an ATA assay result from a baseline sample and/or at least one post-baseline sample.

9. Percentage of Participants With Total Pathologic Complete Response (tpCR), Evaluated After Surgery [After completion of neoadjuvant treatment and surgery (up to 25 weeks)]

   Total pathologic complete response (tpCR) was the pCR based on tumor and nodal staging (i.e., histological confirmation of pCR in breast and nodes at surgery) and was defined as the absence of any residual invasive cancer in the breast and the absence of any metastatic cells in the regional lymph nodes (i.e., ypT0/is ypN0 tpCR). Participants who did not undergo surgery or did not have a valid pCR assessment were considered non-responders in the analysis. The 95% CIs were calculated using the Clopper-Pearson method.

10. Percentage of Participants With Clinical Response as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 During the Neoadjuvant Treatment Period [From Baseline until disease progression or death due to any cause up to 24 weeks (during the neoadjuvant treatment period; assessed on Day 1 of Cycles 1-8 [cycle length=2-3 weeks])]

    The clinical response rate was defined as the percentage of participants in the ITT population who achieved a complete response (CR) or partial response (PR) prior to surgery, according to RECIST v1.1. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the longest diameter compared to Baseline. Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient (20%) increase to qualify for disease progression, in addition to no new target lesions. Progressive Disease (PD): at least a 20% increase in the sum of the longest diameter, taking as reference the smallest sum of the longest diameter observed at previous tumor assessment, or the appearance of any new lesions. Participants were classified as missing or unevaluable if no assessments were measured prior to surgery on the ipsilateral breast. The 95% CIs were calculated using the Clopper-Pearson method; they were only calculated for responses (not for missing or unevaluable data).

11. Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Event-Free Survival (EFS) at 1 to 5 Years, Determined by the Investigator According to RECIST v1.1 [At 1, 2, 3, 4, and 5 years]

    The Kaplan-Meier method was used to estimate the percentage of participants who were event-free at landmark timepoints. Event-free survival (EFS) was defined as the time from enrollment to the first occurrence of progressive disease (PD), relapse, or death from any cause, with tumor evaluations performed by the investigator according to RECIST v1.1. Ipsilateral or contralateral in situ disease and second primary non-breast cancers (including in situ carcinomas and non-melanoma skin cancers) were not counted as progressive disease or relapse. Participants who withdrew from the study without documented progression or relapse and for whom there existed evidence that evaluations had been made, were censored at the date of the last assessment at which the participant was known to be free from progressive disease or relapse. Participants with no tumor evaluations after baseline were censored at the date of enrollment plus 1 day.

12. Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Invasive Disease-Free Survival (iDFS) at 1 to 4 Years, Determined by the Investigator According to RECIST v1.1 [At 1, 2, 3, and 4 years]

    The Kaplan-Meier method was used to estimate the percentage of participants who were event-free at landmark timepoints. Invasive disease-free survival (iDFS) was defined as the time from the first date of no disease (the date of surgery) to the first documentation of progressive invasive disease, relapse, or death, with tumor evaluations performed by the investigator according to RECIST v1.1. Ipsilateral or contralateral in situ disease and second primary non-breast cancers (including in situ carcinomas and non-melanoma skin cancers) were not counted as progressive disease or relapse. Participants who withdrew from the study without documented progression or relapse and for whom there existed evidence that evaluations had been made, were censored at the date of the last assessment at which the participant was known to be alive and disease-free. Participants with no postbaseline information and participants who did not undergo surgery were excluded from the analysis.

13. Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Overall Survival (OS) at 1 to 5 Years [At 1, 2, 3, 4, and 5 years]

    The Kaplan-Meier method was used to estimate the percentage of participants who were event-free at landmark timepoints. Overall survival (OS) was defined as the time from enrollment to death from any cause. Participants who were alive or lost to follow-up were censored at their last known date in the study. Participants with no post-baseline assessments were censored at the date of enrollment plus 1 day.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female participants with locally advanced, inflammatory, or early-stage, unilateral, and histologically confirmed invasive breast cancer. Participants with inflammatory breast cancer must be able to have a core needle biopsy

• Primary tumor greater than (>) 2 centimeters (cm) in diameter, or > 5 millimeters (mm) in diameter and node-positive

• HER2-positive breast cancer confirmed by a central laboratory

• Availability of tumor tissue specimen

• Baseline LVEF greater than or equal to (>/=) 55%

• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (</=) 1

• At least 4 weeks since major unrelated surgery, with full recovery

• Women of childbearing potential and male participants with partners of childbearing potential must agree to use a "highly effective" non-hormonal form of contraception or two "effective" forms of non-hormonal contraception by the patient and/or partner. Contraception must continue for the duration of study treatment and for at least 7 months after the last dose of study treatment

Exclusion Criteria:

• Metastatic disease (Stage IV) or bilateral breast cancer

• Participants who have had an incisional biopsy of the primary tumor or the primary tumor excised

• Prior breast or non-breast malignancy within 5 years prior to study entry, except for carcinoma in situ and basal cell and squamous cell carcinoma of the skin. Participants with malignancies occurring more than 5 years prior to study entry are permitted if curatively treated

• Any previous systemic therapy (including chemotherapy, immunotherapy, HER2 targeted agents, and antitumor vaccines) for cancer, or radiation therapy for cancer

• Participants with a past history of ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS) are not allowed to enter the study if they have received any systemic therapy for its treatment or radiation therapy to the ipsilateral breast (they are allowed to enter the study if treated with surgery alone)

• High-risk participants who have received chemopreventive drugs in the past are not allowed to enter the study

• Inadequate bone marrow, renal, or liver function

• History or evidence of cardiovascular condition

• Dyspnea at rest or other diseases that require continuous oxygen therapy

• Severe, uncontrolled systemic disease

• Participants with poorly controlled diabetes or with evidence of clinically significant diabetic vascular complications

• Pregnancy or breast-feeding women

• Participants who received any investigational treatment within 4 weeks of study start

• Participants with known infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus

• Current chronic daily treatment with corticosteroids (dose >10 mg methylprednisolone or equivalent [excluding inhaled steroids])

• Known hypersensitivity to any of the study drugs or excipients

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of South Alabama; Mitchell Cancer Institute	Mobile	Alabama	United States	36604
2	Marin Specialty Care	Greenbrae	California	United States	94904
3	California Pacific Medical Center	San Francisco	California	United States	94115
4	MedStar Georgetown University Hospital (Lombardi Comprehensive Cancer Center)	Washington	District of Columbia	United States	20007
5	Washington Cancer Institute at MedStar Washington Hospital Center.	Washington	District of Columbia	United States	20010
6	Cancer Specialists; North Florida ;Jacksonville (AC Skinner Pkwy)	Jacksonville	Florida	United States	32256
7	Northwest Georgia Oncology Centers PC - Marietta	Marietta	Georgia	United States	30060
8	Berkshire Medical Center	Pittsfield	Massachusetts	United States	01201
9	Allina Health, Virginia Piper Cancer Institute	Minneapolis	Minnesota	United States	55407
10	Saint Lukes Hospital Cancer Institute	Kansas City	Missouri	United States	64111
11	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
12	Regional Cancer Care Associates LLC - Morristown	Morristown	New Jersey	United States	07962
13	San Juan Oncology Associates	Farmington	New Mexico	United States	87401
14	MSKCC @ Commack	Commack	New York	United States	11725
15	MSKCC @ West Harrison	Harrison	New York	United States	10604
16	Mount Sinai Beth Israel Comprehensive Cancer Center	New York	New York	United States	10011
17	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
18	MSKC @ Rockville	Rockville Centre	New York	United States	11570
19	Mercy Clinic Oklahoma Communties, Inc	Oklahoma City	Oklahoma	United States	73120
20	Harrington Cancer Center	Amarillo	Texas	United States	79106
21	University of Utah; Huntsman Cancer Hospital	Salt Lake City	Utah	United States	84112
22	Blue Ridge Cancer Care	Roanoke	Virginia	United States	24014
23	PeaceHealth St. Joseph Cancer Center	Bellingham	Washington	United States	98225
24	Northwest Medical Specialties	Tacoma	Washington	United States	98405
25	Horizon Health Network	Moncton	New Brunswick	Canada	E1C 6Z8
26	Royal Victoria Hospital	Barrie	Ontario	Canada	L4M 6M2
27	Cite de La Sante de Laval; Hemato-Oncologie	Laval	Quebec	Canada	H7M 3L9
28	St Mary's Hospital Center	Montreal	Quebec	Canada	H3T1M5
29	Hopital Sacre-Coeur Research Centre	Montreal	Quebec	Canada	H4J 1C5
30	Allan Blair Cancer Centre	Regina	Saskatchewan	Canada	S4T 7T1
31	Herlev Hospital; Afdeling for Kræftbehandling	Herlev		Denmark	2730
32	Rigshospitalet; Onkologisk Klinik	København Ø		Denmark	2100
33	Vejle Sygehus; Onkologisk Afdeling	Vejle		Denmark	7100
34	Clinique Victor Hugo; Chimiotherapie	Le Mans		France	72015
35	Centre Oscar Lambret; Cancerologie Gynecologique	Lille		France	59020
36	Centre Leon Berard; Departement Oncologie Medicale	Lyon		France	69373
37	Clinique Clementville; Hopital De Jour	Montpellier		France	34070
38	Centre D'Oncologie de Gentilly; Oncology	Nancy		France	54100
39	Centre Antoine Lacassagne; Hopital De Jour A2	Nice		France	06189
40	Institut Curie; Oncologie Medicale	Paris		France	75231
41	Centre Eugene Marquis; Unite Huguenin	Rennes		France	35042
42	Institut Gustave Roussy; Departement Oncologie Medicale	Villejuif		France	94805
43	Universitätsklinikum "Carl Gustav Carus"; Frauenheilkunde und Geburtshilfe	Dresden		Germany	01307
44	Dres.Andreas Ammon und Dirk Meyer	Göttingen		Germany	37073
45	Dres. Andreas Köhler und Roswitha Fuchs	Langen		Germany	63225
46	Klinikum rechts der Isar der TU München; Klinik und Poliklinik für Frauenheilkunde	München		Germany	81675
47	Ruppiner Kliniken, Klinik fuer Gynaekologie und Geburtshilfe	Neuruppin		Germany	16816
48	Policlinico Umberto i di Roma; dip. Scienze Radiologiche, Oncologiche, Anatomopatologiche	Roma	Lazio	Italy	00161
49	A.O. Città della Salute e della Scienza - Presidio Molinette; divisione oncologia medica	Torino	Piemonte	Italy	10126
50	Asl Le-Ospedale "Vito Fazzi";U.O. Oncologia	Lecce	Puglia	Italy	73100
51	Casa Di Cura Di Alta Specialita La Maddalena; Dept. Oncologico Di Iii Livello	Palermo	Sicilia	Italy	90146
52	Ospedale Santa Maria Annunziata; Oncologia	Bagno a Ripoli	Toscana	Italy	50012
53	Ospedale Della Misericordia; U.O. Di Medicina Ia - Oncologia Medica	Grosseto	Toscana	Italy	58100
54	Iem-Fucam	D.f.		Mexico	04980
55	Centro de Diagnóstico y Tratamiento Integral de Mama, Hospital San José Tec de Monterrey	Monterrey		Mexico	64710
56	Haukeland Universitetssjukehus; Klinisk forskningspost	Bergen		Norway	5021
57	Oslo universitetssykehus HF, Ullevål, Kreftsenteret	Oslo		Norway	0450
58	Bialostockie Centrum Onkologii; Oddzial Onkologii Klinicznej	Bialystok		Poland	15-027
59	Szpital Uniwersytecki w Krakowie, Oddział Kliniczny Kliniki Onkologii	Kraków		Poland	30-688
60	Europejskie Centrum Zdrowia Otwock Szpital im. Fryderyka Chopina, Klinika Onkologii	Otwock		Poland	05-400
61	Wielkopolskie Centrum Onkologii; im. Marii Skłodowskiej-Curie	Poznan		Poland	61-866
62	Centro Clinico Champalimaud; Oncologia Medica	Lisboa		Portugal	1400-038
63	Hospital de Santa Maria; Servico de Oncologia Medica	Lisboa		Portugal	1649-035
64	Hospital Beatriz Angelo; Departamento de Oncologia	Loures		Portugal	2674-514
65	IPO do Porto; Servico de Oncologia Medica	Porto		Portugal	4200-072
66	Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia	Badalona	Barcelona	Spain	08916
67	Hospital Universitario Reina Sofia; Servicio de Oncologia	Córdoba	Cordoba	Spain	14004
68	Centro Oncológico Gallego José Antonio Quiroga y Piñeiro, Servicio de Oncologia	La Coruña		Spain	15009
69	Hospital Universitario de la Princesa; Servicio de Oncologia	Madrid		Spain	28006
70	Hospital Ramon y Cajal; Servicio de Oncologia	Madrid		Spain	28034
71	Hospital Universitario Virgen Macarena; Servicio de Oncologia	Sevilla		Spain	41009
72	Complejo Hospitalario de Toledo- H. Virgen de la Salud; Servicio de Oncologia	Toledo		Spain	45004
73	Royal United Hospital; Oncology Department	Bath		United Kingdom	BA1 3NG
74	Royal Bournemouth Hospital; Oncology	Bournemouth		United Kingdom	BH7 7DW
75	Guys & St Thomas Hospital; Department of Oncology	London		United Kingdom	SE1 9RT
76	Royal Marsden Hospital - Fulham; Oncology Department	London		United Kingdom	SW3 6JJ
77	Freeman Hospital; Northern Centre For Cancer Care	New Castle Upon Tyne		United Kingdom	NE7 7DN
78	Churchill Hospital; Oxford Cancer and Haematology Centre	Oxford		United Kingdom	OX3 7LJ
79	Peterborough City Hospital, Edith Cavell Campus; Oncology Department	Peterborough		United Kingdom	PE3 9GZ
80	Royal Marsden Hospital; Dept of Medical Oncology	Sutton		United Kingdom	SM2 5PT

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02132949
• Other Study ID Numbers: WO29217; 2014-000156-28
• First Posted: May 7, 2014
• Last Update Posted: Sep 17, 2021
• Last Verified: Aug 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel; Docetaxel; Cyclophosphamide; Doxorubicin; Fluorouracil; Trastuzumab; Epirubicin; Pertuzumab

Study Results

Participant Flow

Pre-assignment Detail	A total of 401 participants were enrolled, 199 in Cohort A and 202 in Cohort B. One participant in Cohort B who was human epidermal growth factor receptor 2 (HER2) negative and was enrolled by error, was excluded. Hence, 199 participants were included in Cohort A and 201 participants in Cohort B.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Period Title: Overall Study
STARTED	199	201
Received Any Cohort A Study Treatment	198	1
Received Any Cohort B Study Treatment	0	198
Underwent Surgery	187	194
Completed Neoadjuvant Treatment (25 Weeks)	182	189
Started Adjuvant Treatment	181	190
Completed Adjuvant Treatment (Up to 39 Weeks)	163	176
Started Treatment-Free Follow-Up (Up to 5 Years)	195	195
COMPLETED	158	173
NOT COMPLETED	41	28

Baseline Characteristics

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab	Total
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Total of all reporting groups
Overall Participants	199	201	400
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.8 (11.7)	49.5 (11.5)	49.6 (11.6)
Sex: Female, Male (Count of Participants)
Female	199 100%	200 99.5%	399 99.8%
Male	0 0%	1 0.5%	1 0.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	24 12.1%	46 22.9%	70 17.5%
Not Hispanic or Latino	147 73.9%	114 56.7%	261 65.3%
Unknown or Not Reported	28 14.1%	41 20.4%	69 17.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	6 3%	0 0%	6 1.5%
Asian	5 2.5%	4 2%	9 2.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	11 5.5%	0 0%	11 2.8%
White	162 81.4%	163 81.1%	325 81.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	15 7.5%	34 16.9%	49 12.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Neoadjuvant Treatment Period
Description	Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method. Results included events with onset from first dose of pertuzumab/trastuzumab prior to surgery through the day before the first dose of any study drug after surgery. If participant withdrew without entering adjuvant period, results included all events with onset from first dose of pertuzumab/trastuzumab through 42 days after last dose of any study drug or on the day of target surgery whichever was later.
Time Frame	From day of first dose of pertuzumab or trastuzumab until the end of the neoadjuvant treatment period (as defined in the description; up to 25 weeks)

Outcome Measure Data

Analysis Population Description

Safety analysis population of all participants who received any study treatment during the neoadjuvant treatment period, grouped according to treatment received.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Measure Participants	199	198
Number (95% Confidence Interval) [percentage of participants]	1.5 0.8%	0 0%

2. Primary Outcome

Title	Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Neoadjuvant Treatment Period
Description	LVEF significant decline was defined as the decline in LVEF of >/= 10%-points from baseline to an LVEF of < 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method. Results include events with onset from the first dose of pertuzumab or trastuzumab prior to surgery through the day before the first dose of any study drug after surgery. If participant withdrew without entering adjuvant period, results included all events with onset from first dose of pertuzumab or trastuzumab through 42 days after last dose of any study drug or on the day of target surgery whichever is later.
Time Frame	From day of first dose of pertuzumab or trastuzumab until the end of the neoadjuvant treatment period (as defined in the description; up to 25 weeks)

Outcome Measure Data

Analysis Population Description

Safety analysis population of all participants who received any study treatment during the neoadjuvant treatment period, grouped according to treatment received.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Measure Participants	199	198
At Least One LVEF Significant Decline Event (Confirmed+Single)	6.5 3.3%	2.0 1%
At Least One Confirmed LVEF Significant Decline	1.0 0.5%	0.5 0.2%
At Least One Single LVEF Significant Decline	5.5 2.8%	1.5 0.7%

3. Secondary Outcome

Title	Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Adjuvant Treatment Period
Description	Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method. Results included events with onset from the first dose of any study drug after surgery through 42 days after the last dose of any study drug.
Time Frame	From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks)

Outcome Measure Data

Analysis Population Description

Safety analysis population of all participants who started and received any study treatment during the adjuvant treatment period, grouped according to treatment received.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Measure Participants	181	190
Number (95% Confidence Interval) [Percentage of participants]	0 0%	0.5 0.2%

4. Secondary Outcome

Title	Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Adjuvant Treatment Period
Description	LVEF significant decline was defined as the decline in LVEF of >/= 10%-points from baseline to an LVEF of < 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals were calculated using the Clopper-Pearson method. Results included events with onset from the first dose of any study drug after surgery through 42 days after the last dose of any study drug.
Time Frame	From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks)

Outcome Measure Data

Analysis Population Description

Safety analysis population of all participants who started and received any study treatment during the adjuvant treatment period, grouped according to treatment received.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Measure Participants	181	190
At Least One LVEF Significant Decline Event (Confirmed+Single)	7.7 3.9%	10.5 5.2%
At Least One Confirmed LVEF Significant Decline	2.8 1.4%	3.2 1.6%
At Least One Single LVEF Significant Decline	5.0 2.5%	7.4 3.7%

5. Secondary Outcome

Title	Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Treatment-Free Follow-Up Period
Description	Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method.
Time Frame	From 42 days after the last dose of study treatment until the end of treatment-free follow-up (up to 5 years)

Outcome Measure Data

Analysis Population Description

Safety analysis population of all participants who received any study treatment during the study, grouped according to treatment received.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Measure Participants	199	198
Number (95% Confidence Interval) [Percentage of participants]	0 0%	0.5 0.2%

6. Secondary Outcome

Title	Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Treatment-Free Follow-Up Period
Description	LVEF significant decline was defined as the decline in LVEF of >/= 10%-points from baseline to an LVEF of < 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals were calculated using the Clopper-Pearson method.
Time Frame	From 42 days after the last dose of study treatment until the end of treatment-free follow-up (up to 5 years)

Outcome Measure Data

Analysis Population Description

Safety analysis population of all participants who received any study treatment during the study, grouped according to treatment received.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Measure Participants	199	198
At Least One LVEF Significant Decline Event (Confirmed+Single)	6.0 3%	3.5 1.7%
At Least One Confirmed LVEF Significant Decline	3.0 1.5%	1.0 0.5%
At Least One Single LVEF Significant Decline	3.0 1.5%	2.5 1.2%

7. Secondary Outcome

Title	Overview of the Number of Participants With at Least One Adverse Event During the Neoadjuvant Period
Description	An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous with respect to an AE. Severity refers to the intensity of an AE (rated according to NCI-CTCAE v4.0 criteria or, if not listed, the following scale: Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), whereas a serious AE (SAE) is a significant medical event (per standard criteria). Severity and seriousness needed to be independently assessed for each AE that was recorded. Selected AEs for reporting included heart failure (NYHA Class II/III/IV) and asymptomatic declines in LVEF (reported as an AE with the term of ejection fraction decreased). In the results table, multiple occurrences of the same AE in one individual were counted only once. Any AE includes all serious and non-serious AEs.
Time Frame	From first dose of any study drug prior to surgery through the day before the first dose of study drug after surgery (up to 25 weeks)

Outcome Measure Data

Analysis Population Description

Safety analysis population of all participants who received any study treatment during the neoadjuvant treatment period, grouped according to treatment received.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Measure Participants	199	198
Any Adverse Event (AE)	198 99.5%	198 98.5%
NCI-CTCAE Grade 3-5 AE	99 49.7%	108 53.7%
Serious AE	45 22.6%	52 25.9%
Deaths	0 0%	0 0%
Ejection Fraction Decreased (Any Grade)	14 7%	7 3.5%
Heart Failure (Any Grade)	4 2%	0 0%

8. Secondary Outcome

Title	Overview of the Number of Participants With at Least One Adverse Event During the Adjuvant Period
Description	An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous with respect to an AE. Severity refers to the intensity of an AE (rated according to NCI-CTCAE v4.0 criteria or, if not listed, the following scale: Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), whereas a serious AE (SAE) is a significant medical event (per standard criteria). Severity and seriousness needed to be independently assessed for each AE that was recorded. Selected AEs for reporting included heart failure (NYHA Class II/III/IV) and asymptomatic declines in LVEF (reported as an AE with the term of ejection fraction decreased). In the results table, multiple occurrences of the same AE in one individual were counted only once. Any AE includes all serious and non-serious AEs.
Time Frame	From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks)

Outcome Measure Data

Analysis Population Description

Safety analysis population of all participants who started and received any study treatment during the adjuvant treatment period, grouped according to treatment received.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Measure Participants	181	190
Any Adverse Event (AE)	171 85.9%	171 85.1%
NCI-CTCAE Grade 3-5 AE	23 11.6%	40 19.9%
Serious AE	15 7.5%	17 8.5%
Deaths	0 0%	0 0%
Ejection Fraction Decreased (Any Grade)	15 7.5%	20 10%
Heart Failure (Any Grade)	0 0%	2 1%

9. Secondary Outcome

Title	Overview of the Number of Participants With at Least One Adverse Event During the Treatment-Free Follow-Up Period
Description	An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an AE (rated according to NCI-CTCAE v4.0 criteria or, if not listed, the following scale: Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), and a serious AE (SAE) is a significant medical event (per standard criteria). Severity and seriousness were independently assessed for each AE. Selected AEs for reporting included heart failure (NYHA Class II/III/IV) and asymptomatic declines in LVEF (reported as ejection fraction decreased). During TFFU, only heart failure, pregnancies, and non-breast-related second primary malignancies, irrespective of causal relationship with study treatment, and drug-related SAEs were reported. Multiple occurrences of the same AE in 1 subject were counted only once.
Time Frame	From 42 days after the last dose of study treatment until the end of treatment-free follow-up (TFFU; up to 5 years)

Outcome Measure Data

Analysis Population Description

Safety analysis population of all participants who received any study treatment during the study, grouped according to treatment received.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Measure Participants	199	198
Any Adverse Event (AE)	3 1.5%	7 3.5%
NCI-CTCAE Grade 3-5 AE	2 1%	5 2.5%
Serious AE	3 1.5%	7 3.5%
Deaths	7 3.5%	13 6.5%
Ejection Fraction Decreased (Any Grade)	1 0.5%	1 0.5%
Heart Failure (Any Grade)	0 0%	1 0.5%

10. Secondary Outcome

Title	Percentage of Participants Positive for Anti-Therapeutic Antibodies (ATAs) to Pertuzumab at Baseline and Anytime Post-Baseline
Description	ATAs to pertuzumab in serum samples were detected using a validated bridging enzyme-linked immunosorbent assay (ELISA) method. This analysis only included participants with an ATA assay result from a baseline sample and/or at least one post-baseline sample.
Time Frame	Screening (baseline) then prior to pertuzumab infusion (Hour 0) in Cycles 5, 14, 18 thereafter anytime between Cycle 8 Day 21 and surgery, up to treatment completion visit (cycle length=2-3 weeks; up to approximately 1 year, 3 months)

Outcome Measure Data

Analysis Population Description

This analysis only included participants with an ATA assay result from a baseline sample and/or at least one post-baseline sample.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Measure Participants	199	201
At Baseline	1.6 0.8%	2.1 1%
Anytime Post-Baseline	4.6 2.3%	3.6 1.8%

11. Secondary Outcome

Title	Percentage of Participants With Total Pathologic Complete Response (tpCR), Evaluated After Surgery
Description	Total pathologic complete response (tpCR) was the pCR based on tumor and nodal staging (i.e., histological confirmation of pCR in breast and nodes at surgery) and was defined as the absence of any residual invasive cancer in the breast and the absence of any metastatic cells in the regional lymph nodes (i.e., ypT0/is ypN0 tpCR). Participants who did not undergo surgery or did not have a valid pCR assessment were considered non-responders in the analysis. The 95% CIs were calculated using the Clopper-Pearson method.
Time Frame	After completion of neoadjuvant treatment and surgery (up to 25 weeks)

Outcome Measure Data

Analysis Population Description

ITT population: included all participants who were enrolled regardless of whether they received any study treatment, grouped according to the arm to which a participant was enrolled.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Measure Participants	199	201
Number (95% Confidence Interval) [Percentage of participants]	61.8 31.1%	60.7 30.2%

12. Secondary Outcome

Title	Percentage of Participants With Clinical Response as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 During the Neoadjuvant Treatment Period
Description	The clinical response rate was defined as the percentage of participants in the ITT population who achieved a complete response (CR) or partial response (PR) prior to surgery, according to RECIST v1.1. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the longest diameter compared to Baseline. Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient (20%) increase to qualify for disease progression, in addition to no new target lesions. Progressive Disease (PD): at least a 20% increase in the sum of the longest diameter, taking as reference the smallest sum of the longest diameter observed at previous tumor assessment, or the appearance of any new lesions. Participants were classified as missing or unevaluable if no assessments were measured prior to surgery on the ipsilateral breast. The 95% CIs were calculated using the Clopper-Pearson method; they were only calculated for responses (not for missing or unevaluable data).
Time Frame	From Baseline until disease progression or death due to any cause up to 24 weeks (during the neoadjuvant treatment period; assessed on Day 1 of Cycles 1-8 [cycle length=2-3 weeks])

Outcome Measure Data

Analysis Population Description

ITT population: included all participants who were enrolled regardless of whether they received any study treatment, grouped according to the arm to which a participant was enrolled.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Measure Participants	199	201
Clinical Response Rate (CR+PR)	67.3 33.8%	60.2 30%
Complete Response (CR)	39.7 19.9%	23.9 11.9%
Partial Response (PR)	27.6 13.9%	36.3 18.1%
Stable Disease (SD)	7.0 3.5%	10.0 5%
Progressive Disease (PD)	0.5 0.3%	1.0 0.5%
Missing or Unevaluable	25.1 12.6%	28.9 14.4%

13. Secondary Outcome

Title	Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Event-Free Survival (EFS) at 1 to 5 Years, Determined by the Investigator According to RECIST v1.1
Description	The Kaplan-Meier method was used to estimate the percentage of participants who were event-free at landmark timepoints. Event-free survival (EFS) was defined as the time from enrollment to the first occurrence of progressive disease (PD), relapse, or death from any cause, with tumor evaluations performed by the investigator according to RECIST v1.1. Ipsilateral or contralateral in situ disease and second primary non-breast cancers (including in situ carcinomas and non-melanoma skin cancers) were not counted as progressive disease or relapse. Participants who withdrew from the study without documented progression or relapse and for whom there existed evidence that evaluations had been made, were censored at the date of the last assessment at which the participant was known to be free from progressive disease or relapse. Participants with no tumor evaluations after baseline were censored at the date of enrollment plus 1 day.
Time Frame	At 1, 2, 3, 4, and 5 years

Outcome Measure Data

Analysis Population Description

ITT population: included all participants who were enrolled regardless of whether they received any study treatment, grouped according to the arm to which a participant was enrolled. The number analyzed per timepoint represents the number of participants remaining at risk at that timepoint.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Measure Participants	199	201
1 Year	98.47 49.5%	97.48 48.5%
2 Years	95.80 48.1%	92.86 46.2%
3 Years	93.58 47%	90.78 45.2%
4 Years	92.39 46.4%	89.73 44.6%
5 Years	90.84 45.6%	89.20 44.4%

14. Secondary Outcome

Title	Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Invasive Disease-Free Survival (iDFS) at 1 to 4 Years, Determined by the Investigator According to RECIST v1.1
Description	The Kaplan-Meier method was used to estimate the percentage of participants who were event-free at landmark timepoints. Invasive disease-free survival (iDFS) was defined as the time from the first date of no disease (the date of surgery) to the first documentation of progressive invasive disease, relapse, or death, with tumor evaluations performed by the investigator according to RECIST v1.1. Ipsilateral or contralateral in situ disease and second primary non-breast cancers (including in situ carcinomas and non-melanoma skin cancers) were not counted as progressive disease or relapse. Participants who withdrew from the study without documented progression or relapse and for whom there existed evidence that evaluations had been made, were censored at the date of the last assessment at which the participant was known to be alive and disease-free. Participants with no postbaseline information and participants who did not undergo surgery were excluded from the analysis.
Time Frame	At 1, 2, 3, and 4 years

Outcome Measure Data

Analysis Population Description

ITT population: included all participants who were enrolled regardless of whether they received any study treatment, grouped according to the arm to which a participant was enrolled. Participants with no post-baseline information and those who did not undergo surgery were excluded from the analysis. The number analyzed per timepoint represents the number of participants remaining at risk at that timepoint.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Measure Participants	187	194
1 Year	98.91 49.7%	96.34 47.9%
2 Years	95.57 48%	94.25 46.9%
3 Years	94.42 47.4%	91.06 45.3%
4 Years	92.60 46.5%	91.06 45.3%

15. Secondary Outcome

Title	Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Overall Survival (OS) at 1 to 5 Years
Description	The Kaplan-Meier method was used to estimate the percentage of participants who were event-free at landmark timepoints. Overall survival (OS) was defined as the time from enrollment to death from any cause. Participants who were alive or lost to follow-up were censored at their last known date in the study. Participants with no post-baseline assessments were censored at the date of enrollment plus 1 day.
Time Frame	At 1, 2, 3, 4, and 5 years

Outcome Measure Data

Analysis Population Description

ITT population: included all participants who were enrolled regardless of whether they received any study treatment, grouped according to the arm to which a participant was enrolled. The number analyzed per timepoint represents the number of participants remaining at risk at that timepoint.

Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab	Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.	Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Measure Participants	199	201
1 Year	99.48 50%	100.00 49.8%
2 Years	98.96 49.7%	97.94 48.7%
3 Years	97.86 49.2%	96.38 48%
4 Years	97.86 49.2%	94.81 47.2%
5 Years	96.10 48.3%	93.75 46.6%

Adverse Events

Time Frame	From first dose of any study drug until the end of treatment-free follow-up (up to 6 years, 1 month)
Arm/Group Title	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab		Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Arm/Group Description	Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.		Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
All Cause Mortality
	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab		Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/199 (3.5%)		13/198 (6.6%)
Serious Adverse Events
	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab		Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	56/199 (28.1%)		66/198 (33.3%)
Blood and lymphatic system disorders
AGRANULOCYTOSIS	1/199 (0.5%)	1	0/198 (0%)	0
ANAEMIA	1/199 (0.5%)	1	0/198 (0%)	0
BONE MARROW FAILURE	1/199 (0.5%)	1	0/198 (0%)	0
FEBRILE NEUTROPENIA	11/199 (5.5%)	11	27/198 (13.6%)	28
LEUKOPENIA	1/199 (0.5%)	1	0/198 (0%)	0
NEUTROPENIA	1/199 (0.5%)	1	2/198 (1%)	2
PANCYTOPENIA	1/199 (0.5%)	1	1/198 (0.5%)	1
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION	1/199 (0.5%)	1	0/198 (0%)	0
ATRIAL FLUTTER	1/199 (0.5%)	1	0/198 (0%)	0
ATRIAL THROMBOSIS	0/199 (0%)	0	1/198 (0.5%)	1
CARDIAC FAILURE	3/199 (1.5%)	3	4/198 (2%)	4
CARDIAC FAILURE CONGESTIVE	1/199 (0.5%)	1	0/198 (0%)	0
CARDIOGENIC SHOCK	1/199 (0.5%)	1	0/198 (0%)	0
MYOCARDIAL ISCHAEMIA	1/199 (0.5%)	1	0/198 (0%)	0
Gastrointestinal disorders
COLITIS	1/199 (0.5%)	1	0/198 (0%)	0
DIARRHOEA	1/199 (0.5%)	1	11/198 (5.6%)	12
HAEMORRHOIDAL HAEMORRHAGE	0/199 (0%)	0	1/198 (0.5%)	1
NEUTROPENIC COLITIS	1/199 (0.5%)	1	0/198 (0%)	0
ODYNOPHAGIA	1/199 (0.5%)	1	0/198 (0%)	0
PANCREATITIS	1/199 (0.5%)	1	0/198 (0%)	0
PANCREATITIS ACUTE	1/199 (0.5%)	1	0/198 (0%)	0
PROCTALGIA	1/199 (0.5%)	1	0/198 (0%)	0
VOMITING	0/199 (0%)	0	1/198 (0.5%)	1
General disorders
GENERAL PHYSICAL HEALTH DETERIORATION	2/199 (1%)	2	0/198 (0%)	0
MUCOSAL INFLAMMATION	0/199 (0%)	0	1/198 (0.5%)	1
PYREXIA	1/199 (0.5%)	1	4/198 (2%)	5
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME	0/199 (0%)	0	1/198 (0.5%)	1
Hepatobiliary disorders
CHOLECYSTITIS	0/199 (0%)	0	1/198 (0.5%)	1
CHOLELITHIASIS	0/199 (0%)	0	1/198 (0.5%)	1
Immune system disorders
ANAPHYLACTIC REACTION	0/199 (0%)	0	1/198 (0.5%)	1
HYPERSENSITIVITY	1/199 (0.5%)	1	0/198 (0%)	0
Infections and infestations
BREAST CELLULITIS	1/199 (0.5%)	1	0/198 (0%)	0
CELLULITIS	2/199 (1%)	2	0/198 (0%)	0
DEVICE RELATED INFECTION	3/199 (1.5%)	3	0/198 (0%)	0
ERYSIPELAS	0/199 (0%)	0	1/198 (0.5%)	1
GASTROENTERITIS	0/199 (0%)	0	1/198 (0.5%)	1
GASTROENTERITIS VIRAL	1/199 (0.5%)	1	0/198 (0%)	0
GASTROINTESTINAL INFECTION	2/199 (1%)	2	0/198 (0%)	0
LOWER RESPIRATORY TRACT INFECTION	2/199 (1%)	2	0/198 (0%)	0
MASTITIS	2/199 (1%)	4	0/198 (0%)	0
NEUTROPENIC SEPSIS	0/199 (0%)	0	7/198 (3.5%)	7
PERITONITIS	0/199 (0%)	0	1/198 (0.5%)	1
PNEUMONIA	2/199 (1%)	2	1/198 (0.5%)	1
POST PROCEDURAL INFECTION	0/199 (0%)	0	1/198 (0.5%)	1
PSEUDOMONAL BACTERAEMIA	0/199 (0%)	0	1/198 (0.5%)	1
PYELONEPHRITIS	1/199 (0.5%)	1	0/198 (0%)	0
RESPIRATORY TRACT INFECTION	1/199 (0.5%)	1	0/198 (0%)	0
URINARY TRACT INFECTION	3/199 (1.5%)	3	0/198 (0%)	0
VASCULAR DEVICE INFECTION	2/199 (1%)	2	3/198 (1.5%)	3
WOUND INFECTION	0/199 (0%)	0	1/198 (0.5%)	1
Injury, poisoning and procedural complications
INFUSION RELATED REACTION	0/199 (0%)	0	2/198 (1%)	2
POST PROCEDURAL HAEMATOMA	0/199 (0%)	0	1/198 (0.5%)	1
SEROMA	1/199 (0.5%)	1	1/198 (0.5%)	1
WOUND DECOMPOSITION	0/199 (0%)	0	1/198 (0.5%)	1
Investigations
ALANINE AMINOTRANSFERASE INCREASED	1/199 (0.5%)	1	0/198 (0%)	0
EJECTION FRACTION DECREASED	5/199 (2.5%)	5	5/198 (2.5%)	5
NEUTROPHIL COUNT DECREASED	0/199 (0%)	0	1/198 (0.5%)	1
TRANSAMINASES INCREASED	1/199 (0.5%)	1	0/198 (0%)	0
WHITE BLOOD CELL COUNT DECREASED	1/199 (0.5%)	3	0/198 (0%)	0
Metabolism and nutrition disorders
DEHYDRATION	1/199 (0.5%)	1	0/198 (0%)	0
Musculoskeletal and connective tissue disorders
MYALGIA	1/199 (0.5%)	1	0/198 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ADENOCARCINOMA OF COLON	0/199 (0%)	0	1/198 (0.5%)	1
BASAL CELL CARCINOMA	0/199 (0%)	0	1/198 (0.5%)	1
COLON CANCER	0/199 (0%)	0	1/198 (0.5%)	1
LUNG NEOPLASM MALIGNANT	0/199 (0%)	0	1/198 (0.5%)	1
NON-HODGKIN'S LYMPHOMA	0/199 (0%)	0	1/198 (0.5%)	1
PLASMA CELL MYELOMA	0/199 (0%)	0	2/198 (1%)	2
RENAL CANCER	1/199 (0.5%)	1	0/198 (0%)	0
Nervous system disorders
CEREBELLAR SYNDROME	1/199 (0.5%)	1	0/198 (0%)	0
HEADACHE	1/199 (0.5%)	1	1/198 (0.5%)	1
PRESYNCOPE	0/199 (0%)	0	1/198 (0.5%)	1
SYNCOPE	1/199 (0.5%)	1	0/198 (0%)	0
TRANSIENT ISCHAEMIC ATTACK	1/199 (0.5%)	1	0/198 (0%)	0
Psychiatric disorders
DEPRESSION	1/199 (0.5%)	1	0/198 (0%)	0
Renal and urinary disorders
ACUTE KIDNEY INJURY	2/199 (1%)	2	0/198 (0%)	0
Reproductive system and breast disorders
BREAST HAEMATOMA	1/199 (0.5%)	1	1/198 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	2/199 (1%)	2	1/198 (0.5%)	1
PAINFUL RESPIRATION	0/199 (0%)	0	1/198 (0.5%)	1
PNEUMONITIS	1/199 (0.5%)	1	0/198 (0%)	0
PULMONARY EMBOLISM	2/199 (1%)	2	0/198 (0%)	0
Skin and subcutaneous tissue disorders
ERYTHEMA MULTIFORME	1/199 (0.5%)	1	0/198 (0%)	0
SKIN NECROSIS	0/199 (0%)	0	1/198 (0.5%)	1
Surgical and medical procedures
ABORTION INDUCED	1/199 (0.5%)	1	0/198 (0%)	0
Vascular disorders
HAEMATOMA	1/199 (0.5%)	1	0/198 (0%)	0
Other (Not Including Serious) Adverse Events
	Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab		Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	197/199 (99%)		198/198 (100%)
Blood and lymphatic system disorders
ANAEMIA	56/199 (28.1%)	65	64/198 (32.3%)	78
FEBRILE NEUTROPENIA	3/199 (1.5%)	3	10/198 (5.1%)	10
LYMPHOPENIA	5/199 (2.5%)	5	11/198 (5.6%)	16
NEUTROPENIA	43/199 (21.6%)	54	31/198 (15.7%)	43
Cardiac disorders
PALPITATIONS	10/199 (5%)	12	11/198 (5.6%)	12
Ear and labyrinth disorders
VERTIGO	4/199 (2%)	4	10/198 (5.1%)	11
Eye disorders
DRY EYE	13/199 (6.5%)	13	13/198 (6.6%)	13
LACRIMATION INCREASED	20/199 (10.1%)	20	37/198 (18.7%)	37
VISION BLURRED	13/199 (6.5%)	16	2/198 (1%)	2
Gastrointestinal disorders
ABDOMINAL PAIN	12/199 (6%)	12	27/198 (13.6%)	38
ABDOMINAL PAIN UPPER	15/199 (7.5%)	17	31/198 (15.7%)	33
CONSTIPATION	73/199 (36.7%)	87	78/198 (39.4%)	90
DIARRHOEA	143/199 (71.9%)	207	141/198 (71.2%)	238
DRY MOUTH	13/199 (6.5%)	13	17/198 (8.6%)	18
DYSPEPSIA	40/199 (20.1%)	46	35/198 (17.7%)	42
GASTROOESOPHAGEAL REFLUX DISEASE	27/199 (13.6%)	27	6/198 (3%)	6
HAEMORRHOIDS	19/199 (9.5%)	20	22/198 (11.1%)	26
MOUTH ULCERATION	5/199 (2.5%)	5	15/198 (7.6%)	16
NAUSEA	144/199 (72.4%)	181	142/198 (71.7%)	196
ODYNOPHAGIA	7/199 (3.5%)	7	10/198 (5.1%)	13
STOMATITIS	49/199 (24.6%)	53	56/198 (28.3%)	73
VOMITING	46/199 (23.1%)	57	71/198 (35.9%)	107
General disorders
ASTHENIA	41/199 (20.6%)	72	85/198 (42.9%)	130
CHILLS	12/199 (6%)	14	4/198 (2%)	4
FATIGUE	125/199 (62.8%)	151	81/198 (40.9%)	119
INFLUENZA LIKE ILLNESS	7/199 (3.5%)	8	21/198 (10.6%)	24
MUCOSAL INFLAMMATION	46/199 (23.1%)	55	77/198 (38.9%)	106
OEDEMA	5/199 (2.5%)	5	10/198 (5.1%)	10
OEDEMA PERIPHERAL	22/199 (11.1%)	25	28/198 (14.1%)	35
PAIN	16/199 (8%)	18	6/198 (3%)	6
PYREXIA	39/199 (19.6%)	45	39/198 (19.7%)	53
Infections and infestations
CONJUNCTIVITIS	10/199 (5%)	10	16/198 (8.1%)	18
INFLUENZA	8/199 (4%)	9	14/198 (7.1%)	16
NASOPHARYNGITIS	21/199 (10.6%)	30	33/198 (16.7%)	40
ORAL CANDIDIASIS	1/199 (0.5%)	1	10/198 (5.1%)	10
PHARYNGITIS	8/199 (4%)	8	13/198 (6.6%)	14
RHINITIS	7/199 (3.5%)	8	18/198 (9.1%)	19
SINUSITIS	11/199 (5.5%)	12	9/198 (4.5%)	9
UPPER RESPIRATORY TRACT INFECTION	25/199 (12.6%)	28	6/198 (3%)	7
URINARY TRACT INFECTION	32/199 (16.1%)	36	10/198 (5.1%)	11
Injury, poisoning and procedural complications
INFUSION RELATED REACTION	38/199 (19.1%)	42	35/198 (17.7%)	50
PROCEDURAL PAIN	17/199 (8.5%)	18	12/198 (6.1%)	14
RADIATION SKIN INJURY	36/199 (18.1%)	36	58/198 (29.3%)	59
Investigations
ALANINE AMINOTRANSFERASE INCREASED	15/199 (7.5%)	19	13/198 (6.6%)	15
ASPARTATE AMINOTRANSFERASE INCREASED	14/199 (7%)	18	11/198 (5.6%)	12
EJECTION FRACTION DECREASED	22/199 (11.1%)	27	22/198 (11.1%)	27
LYMPHOCYTE COUNT DECREASED	12/199 (6%)	15	0/198 (0%)	0
NEUTROPHIL COUNT DECREASED	18/199 (9%)	22	19/198 (9.6%)	26
WEIGHT DECREASED	19/199 (9.5%)	19	13/198 (6.6%)	13
WHITE BLOOD CELL COUNT DECREASED	22/199 (11.1%)	29	6/198 (3%)	6
Metabolism and nutrition disorders
DECREASED APPETITE	40/199 (20.1%)	42	49/198 (24.7%)	59
DEHYDRATION	10/199 (5%)	14	1/198 (0.5%)	1
HYPOKALAEMIA	16/199 (8%)	18	6/198 (3%)	10
Musculoskeletal and connective tissue disorders
ARTHRALGIA	73/199 (36.7%)	96	67/198 (33.8%)	81
BACK PAIN	30/199 (15.1%)	36	22/198 (11.1%)	25
BONE PAIN	24/199 (12.1%)	27	13/198 (6.6%)	18
MUSCLE SPASMS	32/199 (16.1%)	37	16/198 (8.1%)	16
MUSCULOSKELETAL CHEST PAIN	13/199 (6.5%)	13	6/198 (3%)	6
MUSCULOSKELETAL PAIN	17/199 (8.5%)	18	27/198 (13.6%)	28
MYALGIA	49/199 (24.6%)	57	76/198 (38.4%)	95
PAIN IN EXTREMITY	27/199 (13.6%)	29	30/198 (15.2%)	36
Nervous system disorders
DIZZINESS	33/199 (16.6%)	37	20/198 (10.1%)	22
DYSGEUSIA	37/199 (18.6%)	41	35/198 (17.7%)	44
HEADACHE	70/199 (35.2%)	85	41/198 (20.7%)	48
HYPOAESTHESIA	10/199 (5%)	10	10/198 (5.1%)	10
NEUROPATHY PERIPHERAL	56/199 (28.1%)	60	34/198 (17.2%)	37
PARAESTHESIA	35/199 (17.6%)	44	27/198 (13.6%)	31
PERIPHERAL SENSORY NEUROPATHY	40/199 (20.1%)	44	21/198 (10.6%)	23
Psychiatric disorders
ANXIETY	23/199 (11.6%)	24	18/198 (9.1%)	20
DEPRESSION	23/199 (11.6%)	23	11/198 (5.6%)	11
INSOMNIA	45/199 (22.6%)	52	35/198 (17.7%)	38
Renal and urinary disorders
DYSURIA	15/199 (7.5%)	16	5/198 (2.5%)	5
POLLAKIURIA	13/199 (6.5%)	14	2/198 (1%)	2
Reproductive system and breast disorders
AMENORRHOEA	9/199 (4.5%)	10	10/198 (5.1%)	10
BREAST PAIN	27/199 (13.6%)	28	20/198 (10.1%)	21
VULVOVAGINAL DRYNESS	22/199 (11.1%)	22	14/198 (7.1%)	14
Respiratory, thoracic and mediastinal disorders
COUGH	50/199 (25.1%)	64	27/198 (13.6%)	30
DYSPNOEA	29/199 (14.6%)	33	37/198 (18.7%)	38
EPISTAXIS	54/199 (27.1%)	61	41/198 (20.7%)	45
NASAL CONGESTION	21/199 (10.6%)	23	4/198 (2%)	4
OROPHARYNGEAL PAIN	26/199 (13.1%)	31	21/198 (10.6%)	23
RHINORRHOEA	21/199 (10.6%)	23	22/198 (11.1%)	22
UPPER-AIRWAY COUGH SYNDROME	12/199 (6%)	13	0/198 (0%)	0
Skin and subcutaneous tissue disorders
ALOPECIA	127/199 (63.8%)	127	117/198 (59.1%)	119
DERMATITIS	9/199 (4.5%)	11	12/198 (6.1%)	12
DERMATITIS ACNEIFORM	15/199 (7.5%)	18	9/198 (4.5%)	10
DRY SKIN	31/199 (15.6%)	32	28/198 (14.1%)	29
ERYTHEMA	19/199 (9.5%)	20	32/198 (16.2%)	36
NAIL DISCOLOURATION	31/199 (15.6%)	31	4/198 (2%)	4
NAIL DISORDER	13/199 (6.5%)	13	21/198 (10.6%)	22
NAIL TOXICITY	10/199 (5%)	12	6/198 (3%)	6
ONYCHOCLASIS	3/199 (1.5%)	3	10/198 (5.1%)	10
ONYCHOLYSIS	14/199 (7%)	16	15/198 (7.6%)	15
ONYCHOMADESIS	19/199 (9.5%)	20	5/198 (2.5%)	5
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME	11/199 (5.5%)	11	23/198 (11.6%)	26
PRURITUS	36/199 (18.1%)	42	44/198 (22.2%)	49
RASH	46/199 (23.1%)	52	40/198 (20.2%)	47
RASH MACULO-PAPULAR	19/199 (9.5%)	19	3/198 (1.5%)	3
SKIN HYPERPIGMENTATION	11/199 (5.5%)	11	7/198 (3.5%)	8
Vascular disorders
HOT FLUSH	69/199 (34.7%)	77	48/198 (24.2%)	55
HYPERTENSION	14/199 (7%)	14	12/198 (6.1%)	14
LYMPHOEDEMA	14/199 (7%)	15	16/198 (8.1%)	17

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.